Ex vivo treatment of proliferating human cord blood stem cells with stroma-derived factor-1 enhances their ability to engraft NOD/SCID mice

Ex vivo proliferation of hematopoietic stem cells (HSCs) is important for cellular and gene therapy but is limited by the observation that HSCs do not engraft as they transit S/G(2)/M. Recently identified candidate inhibitors of human HSC cycling are transforming growth factor-beta(1) (TGF-beta(1)) and stroma-derived factor-1 (SDF-1). To determine the ability of these factors to alter the transplantability of human HSCs proliferating in vitro, lin(-) cord blood cells were first cultured for 96 hours in serum-free medium containing Flt3 ligand, Steel factor, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor. These cells were then transferred to medium containing Steel factor and thrombopoietin with or without SDF-1 and/or TGF-beta(1) for 48 hours. Exposure to SDF-1 but not TGF-beta(1) significantly increased (> 2-fold) the recovery of HSCs able to repopulate nonobese diabetic/severe combined immunodeficiency mice. These results suggest new strategies for improving the engraftment activity of HSCs stimulated to proliferate ex vivo.     

Diagnostic accuracy for lupus and other systemic autoimmune diseases in the community setting

BACKGROUND: Most individuals with autoimmune and other immune disorders undergo initial evaluation in the community setting. Since misdiagnosis of systemic autoimmune diseases can have serious consequences, we evaluated community physicians' accuracy in diagnosing autoimmune diseases and the consequences of misdiagnosis. METHODS: We studied the patients referred to our Autoimmune Disease Center for 13 months (n = 476). We estimated the degree of agreement with the final diagnosis (kappa statistic) and the accuracy indexes (sensitivity, specificity, and predictive values) of the referring physicians' diagnoses. RESULTS: We found a 49% agreement between the referring and final diagnoses (kappa = 0.36). Of 263 patients referred with a presumptive diagnosis of systemic lupus erythematosus (SLE), 125 received a diagnosis of other conditions (kappa = 0.34). Of those referred with SLE, 76 (29%) were seropositive for antinuclear antibodies but did not have autoimmune disease. The degree of agreement for referring rheumatologists (kappa = 0.55) was better than that for nonrheumatologists (kappa = 0.32). Stepwise logistic regression indicated that rheumatologists were 4 times more likely to make an accurate diagnosis of SLE than were nonrheumatologists (P<.003). Thirty-nine patients who were seropositive for antinuclear antibodies but had no autoimmune disease had been treated with corticosteroids at dosages as high as 60 mg/d. CONCLUSIONS: Many patients with a positive antinuclear antibody test are incorrectly given a diagnosis of SLE and sometimes treated with toxic medications. The data support the importance of continuing medical education for community physicians in screening for autoimmune diseases and identifying patients who may benefit from early referral to a specialist.     

Frequency and clinicopathological features of fibroelastotic changes in the gastrointestinal tract

Fibroelastotic changes (FEC) and especially elastotic polyps of the gastrointestinal (GI) tract are considered rare benign lesions. They consist of accumulations of elastic fibers within the mucosal, submucosal, or muscular layer, occurring in all parts of the GI tract and often appearing as polyps, but also as diffuse non-polyp-forming deposits. They have been the subject of only a few studies. To explore the clinical and histopathological features of FEC in the GI tract, a series of 162 elastotic lesions was collected within a 2-year period. The clinical data and endoscopic findings were correlated. FEC appeared as polyp-forming lesions of the large intestine in 23 samples (14 %), all other samples concerning histological findings without an identifiable gross mass. Frequently related findings were postinterventional status (9 %), previous irradiation (7 %), and history of GI lymphoma (4 %). Eight samples (5 %) presented endoscopically with lesions justifying surgical intervention. We identified three different histological patterns of FEC, which we have called fibroelastosis, angioelastosis, and elastofibroma. Consistent with previous studies, CD34 immunohistochemical staining (performed on 38 polypoid FEC specimens) showed an increase of CD34-positive mesenchymal cells in 95 % of immunostained samples, suggesting a potential role for CD34-positive mesenchymal cells in the accumulation of elastic fibers. In conclusion, FEC are more common in the GI tract than previously recognized. They often present as a benign polyp. Many accompany other diseases like ulcers and atrophic gastritis or represent a residual finding after an intervention.     

Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations

Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare.     

Mutation of POC1B in a Severe Syndromic Retinal Ciliopathy

We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106Pro_POC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106Pro_POC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD.     

Blood pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project

Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.     

Impact of a prior medical degree on students' dental school performance in Innsbruck, Austria

The purpose of this study was to identify the performance differences between two groups of Austrian dental students (one with a prior medical degree and one without a medical degree) during their dental school training and final dental licensure examination. A specific aim was to determine if having a medical degree is a predictive factor for dental students' scores on the Austrian Dental Admission Test (Austrian DAT), performance in the dental clinic, and scores on final exam. The study consisted of a retrospective analysis of 122 students (thirty-nine with a medical degree and eighty-three without a medical degree) who were enrolled in the Dental Clinic at Innsbruck Medical University, Innsbruck, Austria, between 2001 and 2006. Three performance categories were considered: Austrian DAT results, clinical performance after the first clinical year in dental school, and performance on the final dental licensure examination. Information on students' age, gender, and previous medical degree was collected from official records. Analyses with student's t-test and Pearson's chi-square test revealed that the students with a medical degree had significantly higher Austrian DAT total test scores, grade point averages after the first clinical year, and scores on the final exam. Additionally, those students had significantly better performance on the final exam in prosthodontics and oral and maxillofacial surgery. The linear regression analysis showed that a medical degree had an independent effect on average scores on the final exam, age, and Austrian DAT test scores, while gender showed no statistically significant effect. Overall, the study found that dental students with a prior medical degree had significantly higher Austrian DAT total test scores and performed significantly better in the first clinical year and on the final exam than those without a prior medical degree.     

A comparative study of the secretory IgA immunoglobulins (s.IgA) in mothers and children with SECC versus a caries free group children and their mothers

Early childhood caries (ECC) is recognized as an infectious disease. The first step in its development is primary infection by the bacterium S. mutans which has been identified as the primary etiologic factors in dental caries. Lactobacilli were also found to play a role in the progression of disease. However the underlying mechanism of immune response to caries is unclear. The association between secretory IgA (s.IgA) and cariogenic microorganisms is still controversial. The purpose of this study was to assess the level of salivary IgA in caries free children, and children with SECC and their corresponding mothers. The study also aims at correlating the children's levels to their mothers'. Sixty children and their mothers attending the dental clinic in King Abdulaziz University participated in our study. Their age ranged from 3 - 5 years. The study groups consisted of thirty children with SECC and a control group consisting of thirty caries free children. Children together with their mothers were examined and their caries level was recorded. Stimulated saliva was collected from each participant for immunological assessment. The secretory IgA (s. IgA) level was assessed by ELISA test. Our study has shown that children with SECC and their mothers had higher levels of s. IgA than the caries free children and their mothers. A positive high correlation was found between secretory IgA of mothers and children in both groups.